bims-kimdis 2025-01-05 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–01–05
twelve papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Exogenous ketone bodies and the ketogenic diet as a treatment option for neurodevelopmental disorders.
Physiology of ageing skeletal muscle and the protective effects of exercise.
Is isocaloric intermittent fasting superior to calorie restriction? A systematic review and meta-analysis of RCTs.
Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.
Lipotoxicity-induced upregulation of FIS1 exacerbates mitochondrial fragmentation and promotes NLRP3-dependent pyroptosis in diabetic cardiomyopathy.
PDIA4 targets IRE1α/sXBP1 to alleviate NLRP3 inflammasome activation and renal tubular injury in diabetic kidney disease.
Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals.
Reduced ATP turnover during hibernation in relaxed skeletal muscle.
Inflammatory and Oxidative Patterns Regulated by Theracurmin Intake in an Experimental Model of Hypertrophic Training and Detraining.
Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.
Combined endurance and resistance exercise training in heart failure with preserved ejection fraction: a randomized controlled trial.
New insights into the relationship of mitochondrial metabolism and atherosclerosis.

Front Nutr. 2024 ;11 1485280

Exogenous ketone bodies and the ketogenic diet as a treatment option for neurodevelopmental disorders.

Naomi Elyse Omori, Mantas Kazimieras Malys, Geoffrey Woo, Latt Mansor.

   Background: Despite being the most prevalent neurodevelopmental disorders, there are comparatively few treatment options available to patients presenting with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The ketogenic diet has historically shown therapeutic utility in treating refractory epilepsy, an adjacent neuropsychiatric condition, in children, adolescents and adults. The following review explores preclinical and clinical literature focusing on the therapeutic potential of the ketogenic diet and exogenous ketone body supplementation in treating common neurodevelopmental disorders.
Method: A narrative review of extant literature was conducted across the domains of perinatal nutrition, ASD, and ADHD. Preclinical and clinical studies focusing on the effect of either the ketogenic diet or exogenous ketone supplementation as a treatment option were included for review.
Results: 14 preclinical and 10 clinical studies were included for discussion. Data supporting the use of a ketogenic intervention for neurodevelopmental disorders is mixed. High heterogeneity in study design was noted for preclinical models, ketogenic intervention, and outcomes measured.
Conclusion: Studies evaluating ketogenic interventions for neurodevelopmental disorders remain in their infancy in terms of both the depth and scope of available literature. The safety and tolerability of ketogenic diets and supplements means there would be value in exploring their effectiveness further in clinical studies.

Keywords:  ADHD; ASD; BHB; autism; ketogenic diet; ketone bodies; ketones; neurodevelopment

DOI:  https://doi.org/10.3389/fnut.2024.1485280
J Physiol. 2025 Jan 01.

Physiology of ageing skeletal muscle and the protective effects of exercise.

Christopher W Sundberg.



Keywords:  ageing; contractile function; dynapenia; exercise; muscle metabolism; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1113/JP287926
Nutr Metab Cardiovasc Dis. 2024 Nov 23. pii: S0939-4753(24)00439-3. [Epub ahead of print] 103805

Is isocaloric intermittent fasting superior to calorie restriction? A systematic review and meta-analysis of RCTs.

Mohammed Hamsho, Wijdan Shkorfu, Yazan Ranneh, Abdulmannan Fadel.

   BACKGROUND AND AIM: Intermittent fasting (IF) has been demonstrated to enhance human health through several mechanisms. However, it is still unclear whether those health benefits are independent of caloric restriction (CR)-induced weight loss. This systematic review and meta-analysis aimed to compare isocaloric IF and CR regarding anthropometric measurements, adherence, metabolic profile, inflammatory biomarkers, and adipokines in adults and elderlies.
METHODS AND RESULTS: Comprehensive research was conducted usin four major databases including Embase, PubMed, Scopus, and Google Scholar without date restriction. Mean differences of the change from baseline ± change SD were calculated as the differences between IF and CR groups. Subgroup analysis was performed according to intervention duration (short-, medium-, and long-term). To determine the reliability of our findings, GRADE assessment was performed. As a result, 20 RCTs were included in this systematic review and meta-analysis. IF groups had significant reductions in fat mass (kg) (P = 0.006) and Interleukin-6 (P < 0.00001) in the short term and fat mass (%) (P = 0.0002), waist circumference (P = 0.005), fasting blood insulin (P < 0.00001) and HOMA-IR (P = 0.04) in the long term. CR groups had significantly lower hunger (P = 0.003), fatigue (P = 0.04), and TG (P = 0.03).
CONCLUSIONS: IF may be an effective alternative to CR but is not superior to CR in enhancing human health. Due to the low number of long-term studies, future studies should focus on conducting longitudinal randomized trials comparing IF and CR in different populations, age groups, and IF patterns.

Keywords:  Adherence; Anthropometric measurements; Caloric restriction; GRADE; Intermittent fasting; Isocaloric; Meta-analysis; Metabolic profile

DOI:  https://doi.org/10.1016/j.numecd.2024.103805
Nat Commun. 2025 Jan 02. 16(1): 122

Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.

Kristoffer J Kolnes, Emelie T F Nilsen, Steffen Brufladt, Allison M Meadows, Per B Jeppesen, Øyvind Skattebo, Egil I Johansen, Jesper B Birk, Kurt Højlund, Janne Hingst, Bjørn S Skålhegg, Rasmus Kjøbsted, Julian L Griffin, Anders J Kolnes, Stephen O'Rahilly, Jørgen F P Wojtaszewski, Jørgen Jensen.

Humans have, throughout history, faced periods of starvation necessitating increased physical effort to gather food. To explore adaptations in muscle function, 13 participants (7 males and 6 females) fasted for seven days. They lost 4.6 ± 0.3 kg lean and 1.4 ± 0.1 kg fat mass. Maximal isometric and isokinetic strength remained unchanged, while peak oxygen uptake decreased by 13%. Muscle glycogen was halved, while expression of electron transport chain proteins was unchanged. Pyruvate dehydrogenase kinase 4 (PDK4) expression increased 13-fold, accompanied by inhibitory pyruvate dehydrogenase phosphorylation, reduced carbohydrate oxidation and decreased exercise endurance capacity. Fasting had no impact on 5' AMP-activated protein kinase (AMPK) activity, challenging its proposed role in muscle protein degradation. The participants maintained muscle strength and oxidative enzymes in skeletal muscle during fasting but carbohydrate oxidation and high-intensity endurance capacity were reduced.

DOI: https://doi.org/10.1038/s41467-024-55418-0
Free Radic Biol Med. 2024 Dec 27. pii: S0891-5849(24)01158-4. [Epub ahead of print]

Lipotoxicity-induced upregulation of FIS1 exacerbates mitochondrial fragmentation and promotes NLRP3-dependent pyroptosis in diabetic cardiomyopathy.

Libo Luo, Qingrui Wu, Qingyu Xiao, Yuqiong Chen, Zhanxiang Deng, Chunren Cen, Jijin Lin.

   BACKGROUND: Lipotoxicity is a significant factor in the pathogenesis of diabetic cardiomyopathy (DbCM), a condition characterized by mitochondrial fragmentation and pyroptosis. Mitochondrial fission protein 1 (FIS1) plays a role in mitochondrial fission by anchoring dynamin-related protein 1 (DRP1). However, the specific contribution of FIS1 to DbCM remains unclear. This study aims to clarify how lipotoxicity-induced upregulation of FIS1 affects mitochondrial fragmentation and the mechanisms linking this fragmentation to NLRP3-dependent pyroptosis in DbCM.
METHODS: To model lipotoxicity in DbCM, we used db/db mice and primary neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA) and conducted a series of in vivo and in vitro experiments. Gain- and loss-of-function studies on NRCMs were performed using pharmacological inhibitors and small interfering RNA (siRNA) transfection, and we assessed the expression and function of FIS1, mitochondrial dynamics, mitochondrial reactive oxygen species (mitoROS) production, NLRP3-dependent pyroptosis, and their interrelationships.
RESULTS: Our results show that in the myocardium of db/db mice, NLRP3-dependent pyroptosis is associated with upregulation of FIS1, mitochondrial fragmentation, and increased oxidative stress. In NRCMs subjected to PA, the application of VX-765 and MCC950 to inhibit caspase-1 and NLRP3, respectively, significantly reduced pyroptosis. Additionally, pretreatment with Mito-TEMPO (MT) demonstrated that mitoROS are critical initiators for NLRP3 inflammasome activation and subsequent pyroptosis. Furthermore, PA-induced upregulation of FIS1 exacerbates mitochondrial fragmentation. Downregulation of FIS1 or inhibition of FIS1/DRP1 interaction reversed mitochondrial fragmentation, reduced mitoROS levels, and mitigated pyroptosis.
CONCLUSIONS: Lipotoxicity-induced FIS1 upregulation exacerbates mitochondrial fragmentation through its interaction with DRP1, leading to increased mitoROS production and the initiation of NLRP3-dependent pyroptosis in DbCM. Therefore, targeting FIS1 emerges as a potential therapeutic approach for managing DbCM.

Keywords:  Diabetic cardiomyopathy; FIS1; Inflammation; Lipotoxicity; Mitochondrial fragmentation; Pyroptosis; mitoROS

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.049
Biochim Biophys Acta Mol Basis Dis. 2024 Dec 30. pii: S0925-4439(24)00639-2. [Epub ahead of print] 167645

PDIA4 targets IRE1α/sXBP1 to alleviate NLRP3 inflammasome activation and renal tubular injury in diabetic kidney disease.

Xuan Liu, Donghui Zhou, Yu Su, Hongling Liu, Qiuyue Su, Tianyu Shen, Mianzhi Zhang, Xue Mi, Yuying Zhang, Shijing Yue, Zhujun Zhang, Dekun Wang, Xiaoyue Tan.

  The role of ER stress in the pathogenesis of diabetic kidney diseases (DKD) remains unclear. We employed bioinformatics to identify the UPR pathway activation, inflammation, and programmed cell death patterns in diabetic tubules. Levels of IRE1α/sXBP1 signaling, NLRP3 inflammasome activity and pyroptosis in tubular cells under high glucose conditions were measured. IRE1α knockdown was used to determine its role in glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. PDIA4 overexpression and silencing were used to assess its impact on the IRE1α/sXBP1 pathway. The dynamic interaction among PDIA4, GRP78, and IRE1α under high glucose were analyzed using immunoprecipitation and crosslinking assays. In STZ-induced and db/db mouse models of DKD, the regulatory role of PDIA4 on IRE1α/sXBP1 signaling and diabetic tubular inflammation and injury were evaluated. Our study showed that IRE1α/sXBP1, NLRP3 inflammasome, and pyroptosis are activated in the renal tubules of DKD patients. Induction of IRE1α pathway mediated the glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. Moreover, overexpression of PDIA4 decreased the activation of IRE1α/sXBP1 under high glucose conditions. High glucose leads to the release of GRP78 from IRE1α and an increased interaction between IRE1α and PDIA4. In mouse models of DKD, overexpressing PDIA4 mitigated diabetic tubular injury and inflammation, marked by decreased IRE1α/sXBP1 and NLRP3 inflammasome. In conclusion, our findings demonstrate that high glucose triggers NLRP3 inflammasome and pyroptosis via the IRE1α/sXBP1 pathway in renal tubular cells. Overexpression of PDIA4 suppresses IRE1α signaling by binding to its oligomeric form, implying a promising therapeutic intervention for DKD.

Keywords:  Diabetic Kidney Disease; IRE1α; NLRP3 inflammasome; PDIA4; sXBP1

DOI:  https://doi.org/10.1016/j.bbadis.2024.167645
Sci Adv. 2025 Jan 03. 11(1): eadr8849

Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals.

Dominik Pesta, Evrim Anadol-Schmitz, Theresia Sarabhai, Yvo Op den Kamp, Sofiya Gancheva, Nina Trinks, Oana-Patricia Zaharia, Lucia Mastrototaro, Kun Lyu, Ivo Habets, Yvonne M H Op den Kamp-Bruls, Bedair Dewidar, Jürgen Weiss, Vera Schrauwen-Hinderling, Dongyan Zhang, Rafael Calais Gaspar, Klaus Strassburger, Yuliya Kupriyanova, Hadi Al-Hasani, Julia Szendroedi, Patrick Schrauwen, Esther Phielix, Gerald I Shulman, Michael Roden.

The athlete's paradox states that intramyocellular triglyceride accumulation associates with insulin resistance in sedentary but not in endurance-trained humans. Underlying mechanisms and the role of muscle lipid distribution and composition on glucose metabolism remain unclear. We compared highly trained athletes (ATHL) with sedentary normal weight (LEAN) and overweight-to-obese (OVWE) male and female individuals. This observational study found that ATHL show higher insulin sensitivity, muscle mitochondrial content, and capacity, but lower activation of novel protein kinase C (nPKC) isoforms, despite higher diacylglycerol concentrations. Notably, sedentary but insulin sensitive OVWE feature lower plasma membrane-to-mitochondria sn-1,2-diacylglycerol ratios. In ATHL, calpain-2, which cleaves nPKC, negatively associates with PKCε activation and positively with insulin sensitivity along with higher GLUT4 and hexokinase II content. These findings contribute to explaining the athletes' paradox by demonstrating lower nPKC activation, increased calpain, and mitochondrial partitioning of bioactive diacylglycerols, the latter further identifying an obesity subtype with increased insulin sensitivity (NCT03314714).

DOI: https://doi.org/10.1126/sciadv.adr8849
Nat Commun. 2025 Jan 02. 16(1): 80

Reduced ATP turnover during hibernation in relaxed skeletal muscle.

Cosimo De Napoli, Luisa Schmidt, Mauro Montesel, Laura Cussonneau, Samuele Sanniti, Lorenzo Marcucci, Elena Germinario, Jonas Kindberg, Alina Lynn Evans, Guillemette Gauquelin-Koch, Marco Narici, Fabrice Bertile, Etienne Lefai, Marcus Krüger, Leonardo Nogara, Bert Blaauw.

Hibernating brown bears, due to a drastic reduction in metabolic rate, show only moderate muscle wasting. Here, we evaluate if ATPase activity of resting skeletal muscle myosin can contribute to this energy sparing. By analyzing single muscle fibers taken from the same bears, either during hibernation or in summer, we find that fibers from hibernating bears have a mild decline in force production and a significant reduction in ATPase activity. Single fiber proteomics, western blotting, and immunohistochemical analyses reveal major remodeling of the mitochondrial proteome during hibernation. Furthermore, using bioinformatical approaches and western blotting we find that phosphorylated myosin light chain, a known stimulator of basal myosin ATPase activity, is decreased in hibernating and disused muscles. These results suggest that skeletal muscle limits energy loss by reducing myosin ATPase activity, indicating a possible role for myosin ATPase activity modulation in multiple muscle wasting conditions.

DOI: https://doi.org/10.1038/s41467-024-55565-4
Int J Sport Nutr Exerc Metab. 2025 Jan 02. 1-11

Inflammatory and Oxidative Patterns Regulated by Theracurmin Intake in an Experimental Model of Hypertrophic Training and Detraining.

Washington Martins Pontes, Vitória Louise, Tatiana Prata Menezes, Guilherme de Paula Costa, Daniel Malta Oliveira, Sirlaine Pio, Fernanda Carolina Ribeiro Dias, Luiz Otávio Guimarães Ervilha, Maria Laura da Cruz Castro, Patrícia Regina Soares de Souza, Daniela Caldeira Costa, Kelerson Mauro de Castro Pinto, André Talvani.

  Dietary supplements have improved performance and muscle hypertrophy in athletes and nonathletes in the past few decades. Theracurmin, a nutraceutical supplement based on curcumin, has been highlighted by its anti-inflammatory and antioxidant properties in physiological and pathological conditions. This study aimed to investigate the effects of theracurmin intake (300 mg/kg), containing 30 mg/kg of curcumin, in male Swiss mice (n = 66) under distinct protocols of climbing stairs (strength exercise) and their respective detraining period. Animals, aged 7-9 weeks, were trained for 8 weeks (5 days/week), with a minimum interval of 24 hr between each session, followed by a 4-week detraining period. After euthanasia, skeletal muscle hypertrophy was evaluated through histological analysis. Tissue inflammatory release of tumor necrosis factor, interleukin (IL)-6, IL-10, and chemokine C-C motif ligand 2, as well as the activity of oxidative stress enzymes (catalase, superoxide dismutase, and lipid peroxidation), were also assessed. In trained animals, inflammatory mediators and skeletal muscle mass increased after training (p = .0004). Theracurmin did not revert the muscle hypertrophy, but it decreased tissue chemokine C-C motif ligand 2 (p = .0001) and lipid peroxidation (p < .0001) after strength training and after detraining (p = .0008 and p = .001, respectively). Tissue tumor necrosis factor was only reduced during the detraining period (p = .037), whereas IL-6 (p = .0001) and IL-10 (p < .0001) increased after the training protocol. No differences were observed in catalase and superoxide dismutase. Our data suggest that theracurmin intake contributes to the reduction of tissue inflammatory mediators during strength training and/or detraining without essential activity on skeletal muscle hypertrophy.

Keywords:  curcumin; hypertrophy; inflammation; resistance training; strength training

DOI:  https://doi.org/10.1123/ijsnem.2024-0143
Nat Commun. 2024 Dec 30. 15(1): 10786

Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.

Qu Tian, Erin E Greig, Christos Davatzikos, Bennett A Landman, Susan M Resnick, Luigi Ferrucci.

Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, kPCr) is associated with less ventricular enlargement and brain aging progression, and less atrophy in specific regions, notably primary sensorimotor cortex, temporal white and gray matter, thalamus, occipital areas, cingulate cortex, and cerebellum white matter. Higher kPCr is also associated with less microstructural integrity decline in white matter around cingulate, including superior longitudinal fasciculus, corpus callosum, and cingulum. Higher in vivo muscle oxidative capacity is associated with preserved brain structure up to over a decade, particularly in areas important for cognition, motor function, and sensorimotor integration.

DOI: https://doi.org/10.1038/s41467-024-55009-z
Nat Med. 2025 Jan 02.

Combined endurance and resistance exercise training in heart failure with preserved ejection fraction: a randomized controlled trial.

Frank Edelmann, Rolf Wachter, André Duvinage, Stephan Mueller, Isabel Fegers-Wustrow, Silja Schwarz, Jeffrey W Christle, Elisabeth Pieske-Kraigher, Melchior Seyfarth, Markus Knapp, Marcus Dörr, Kathleen Nolte, Hans-Dirk Düngen, Christoph Herrmann-Lingen, Katrin Esefeld, Andreas Hagendorff, Mark J Haykowsky, Gerd Hasenfuss, Volker Holzendorf, Christiane Prettin, Meinhard Mende, Burkert Pieske, Martin Halle.

Endurance exercise training (ET) is an effective treatment in heart failure with preserved ejection fraction (HFpEF), but the efficacy of resistance training in this patient population has been only scarcely evaluated. In this multicenter, randomized trial, we evaluated the effects of combined endurance and resistance training over 12 months in patients with HFpEF. The primary endpoint was a modified Packer score, including all-cause mortality, hospitalizations classified as potentially related to heart failure or exercise and changes in peak oxygen consumption ( V̇O2 ), diastolic function (E/e'), New York Heart Association (NYHA) class and global self-assessment (GSA). In total, 322 patients (mean age, 70 years; 192 females (59.6%) and 130 males (40.4%)) were randomized (1:1) to ET or usual care (UC). At 12 months, the modified Packer score showed an improvement in 33 ET patients (20.5%) and in 13 UC patients (8.1%) and showed a worsening in 69 ET patients (42.9%) and in 71 UC patients (44.1%) (Kendall's tau-b = -0.073, P = 0.17). Although the primary endpoint was not met, clinically relevant differences favoring the ET group as compared to the UC group were observed for the following secondary endpoints: changes in peak V̇O2 (mean difference, 1.3 ml kg-1 min-1 (95% confidence interval (CI): 0.4-2.1)) and NYHA class (odds ratio = 7.77 (95% CI: 3.73-16.21)). No significant between-group differences were observed for other secondary endpoints, including change in E/e', change in GSA, time to cardiovascular hospitalization or all-cause mortality. In conclusion, 1 year of combined endurance and resistance ET did not result in a significantly better modified Packer score, but it did result in improvements in important clinical parameters, such as peak V̇O2 and NYHA class, as compared to UC. ISRCTN registration: ISRCTN86879094 .

DOI: https://doi.org/10.1038/s41591-024-03342-7
Cell Signal. 2024 Dec 26. pii: S0898-6568(24)00556-4. [Epub ahead of print]127 111580

New insights into the relationship of mitochondrial metabolism and atherosclerosis.

Zexun Wang, Wangqing Sun, Kai Zhang, Xianjin Ke, Zhongqun Wang.

  Atherosclerotic cardiovascular and cerebrovascular diseases are the number one killer of human health. In view of the important role of mitochondria in the formation and evolution of atherosclerosis, our manuscript aims to comprehensively elaborate the relationship between mitochondria and the formation and evolution of atherosclerosis from the aspects of mitochondrial dynamics, mitochondria-organelle interaction (communication), mitochondria and cell death, mitochondria and vascular smooth muscle cell phenotypic switch, etc., which is combined with genome, transcriptome and proteome, in order to provide new ideas for the pathogenesis of atherosclerosis and the diagnosis and treatment of related diseases.

Keywords:  Atherosclerosis; Mitochondria dynamics; Mitochondria epigenetics; Sirtuin family

DOI:  https://doi.org/10.1016/j.cellsig.2024.111580